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July 2, 2002


Brain Cell Death in Huntington's Disease: Emory Researchers Study the Causes

Huntington's disease (HD) is a hereditary disorder of the central nervous system that develops in adulthood and can cause of a wide range of symptoms. A faulty gene which produces a protein called huntingtin causes HD. That faulty gene leads to damage of the brain cells or neurons, then gradual physical, mental and emotional changes follow.

Researchers at Emory University, along with researchers at Duke University and University of British Columbia, Canada, are trying to determine how and why these neurons die and what role the mutant huntingtin protein plays in killing these brain cells. The findings will appear in the electronic publication of Nature Neuroscience on July 1, 2002, and in a later print publication of the journal.

"I think there is little doubt that the mutant huntingtin protein does several different harmful things to neurons," says J. Timothy Greenamyre, M.D., Ph.D., medical director of the Huntington's Disease Society of America (HDSA) Center of Excellence at Emory University and professor of neurology, Emory University School of Medicine. "The huntingtin protein dramatically alters which cellular genes turn on and off, activates cell death pathways and alters mitochondrial function. At first glance, this might seem to make our attempts to unravel HD terribly difficult, but it also presents more 'targets' at which we can aim new treatments," Dr. Greenamyre explains.

Dr. Greenamyre's lab is studying the mitochondrial function in HD. Mitochondria produce energy for the cells. Past studies have shown that mitochondria in HD do not function properly. "By impairing the function of mitochondria in lab rodents, we have noticed the brain cells that die in the rodents are the same cells that die in Huntington's disease," says Dr. Greenamyre. "This finding helps us to reproduce many of the features of HD."

Besides producing energy for the cell, normal mitochondria also help to regulate calcium levels within neurons, preventing the levels from rising too high, which can cause cell damage or death. Mitochondria in HD have problems with this regulation process and, in turn, release calcium and other harmful chemicals into the cell interior. The results are cell damage and death. Dr. Greenamyre describes normal mitochondria as having a charge like a battery. When the battery runs down, he explains the process is similar to mitochondria in HD. The mitochondria in HD do not have a full charge, he says. The Emory researchers have also discovered that HD mitochondria depolarize or short-circuit differently from normal mitochondria.

"Our research has also helped us determine how the mutant huntingtin protein alters mitochondrial function," Dr. Greenamyre points out. "By exposing normal mitochondria to the mutant huntingtin protein, we've found they begin to behave like HD mitochondria. They can no longer take up a normal amount of calcium and they begin to short-circuit when the calcium levels are too low."

More studies still need to be conducted to better define these mitochondrial abnormalities. However, Dr. Greenamyre's research suggests that medications designed to improve mitochondrial function should be beneficial in patients with Huntington's disease. Whether those patients should be given the drugs when the abnormal gene is recognized or wait until the disease further progresses, is still unknown.

Right now, doctors can only treat the symptoms of Huntington's disease, which include involuntary movements, loss of intellectual faculties, difficulty in speech and swallowing, mood swings and depression. Currently there is no cure for the illness. About 30,000 Americans have HD and about 150,000 more are at risk of inheriting the disease from a parent.

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